Approach
Most asymptomatic people may be observed without the need for treatment.
For patients aged younger than 60 years with cryptogenic stroke, percutaneous closure of PFO with antiplatelet therapy is recommended to decrease the risk of future ischemic events. For such patients who have indications for chronic anticoagulation, PFO device closure is not recommended.
Evidence for PFO closure in patients older than 60 years, with multiple cardiovascular risk factors, is not as strong.
Guidelines support a multidisciplinary approach with involvement of neurology and cardiology teams, along with shared decision making with the patient, in formulating a management plan.[22][23] Various stroke guidelines offer guidance on management approach to patients with cryptogenic stroke and PFO; these should be referred to in formulating a management plan for these patients.[22][23][24][25]
It is unclear whether patients with recurrent migraine headaches or decompression sickness would benefit from routine evaluation and closure of their PFO.
Asymptomatic patients with low embolism risk (not in high-risk occupation)
Some PFOs are detected as an incidental finding on echo. The size of the defect and the number of microbubbles crossing into the left atrium seem to define relative risk. A small number of microbubbles (<10) crossing over generally indicates a small defect and is associated with a lower risk of thromboembolism. However, the number of microbubbles crossing over can be variable depending on certain factors. Factors that may increase the number of bubbles seen to cross are injection through a lower limb vein instead of an upper limb vein, and evaluation during Valsalva or coughing. The number of bubbles may also be somewhat influenced by the density of microbubbles in the injectate.
In asymptomatic patients judged to have a low embolism risk, conservative treatment comprising patient education and short-term observation for any evidence of a paradoxical embolism is usually sufficient.
Asymptomatic patients with high risk of thrombotic event (not in high-risk occupation)
Individual assessment of risk is recommended. Clinical observation may be appropriate care in selected patients. There is some evidence to suggest that larger PFO defects and associated atrial septal aneurysms carry a higher risk of cerebrovascular accident.[26][27]
Initiation of antiplatelet therapy with aspirin or clopidogrel may be considered and referral to an appropriate specialist is also recommended. Anticoagulation with warfarin is less commonly recommended, but may be considered. There are no clear guidelines on combined usage, although a combination is often used in patients with concomitant coronary artery disease.
Cryptogenic stroke
For the management of patients with non-lacunar cryptogenic stroke and PFO, a multidisciplinary approach is warranted to evaluate for cryptogenic stroke and the probability of PFO as a contributing factor for the event. Workup includes evaluation for atrial fibrillation, aortic or cerebrovascular disease, and left heart disease.
In patients ages 18 to 60 years with established cryptogenic stroke and presence of PFO, it is reasonable to proceed with a percutaneous transcatheter PFO closure procedure along with postoperative antiplatelet therapy to prevent recurrent ischemic events, rather than antiplatelet therapy alone.[25] The benefit with PFO closure appears stronger in patients with high-risk features (i.e., large PFO, atrial septal aneurysm).[22]
In patients with low-risk anatomic features of PFO, further risk stratification using the risk of paradoxical embolism (RoPE) score might be beneficial in identifying patients with PFO-related cryptogenic stroke. Factors in the score indicative of a higher likelihood of a PFO-related stroke are the absence of traditional risk factors such as hypertension and diabetes mellitus, prior stroke, cortical infarct on imaging, and younger age.[28] Prior to percutaneous closure, patients receive antiplatelet therapy or anticoagulation. After PFO closure, antiplatelet therapy is typically recommended. For patients who have indications for chronic anticoagulation, PFO device closure is not indicated.
The PFO procedure is associated with a benefit of an absolute recurrent stroke risk reduction of 3.4% at 5 years, with a periprocedural complication risk of 3.9% and increased absolute rate of nonperiprocedural atrial fibrillation of 0.33% per year.[28]
Evidence is not as strong for PFO closure in patients younger than 18 years or older than 60 years with multiple cardiovascular risk factors. Guidelines support a multidisciplinary approach with involvement of neurology and cardiology teams, along with shared decision making with the patient, in formulating a management plan.[22][23]
For patients with cryptogenic stroke, who are not a candidate for a PFO closure procedure, medical therapy with full anticoagulation is preferred over antiplatelet therapy to decrease recurrent ischemic events. This approach is associated with an increased risk of major bleeding. Careful evaluation of the bleeding profile of the patient and shared decision making is recommended in selecting antiplatelet versus anticoagulation therapy.[25]
Similarly, in patients with planned long-term anticoagulation, an additional benefit of PFO closure for reducing ischemic events is not established.
High-risk occupation
In patients involved in a high-risk profession (e.g., an astronaut, deep sea diver, or high altitude pilot), treatment with antiplatelet or anticoagulation therapy is generally recommended, along with behavioral prevention of decompression sickness.[29] Percutaneous closure of the PFO should be considered on an individual basis for scuba divers who have symptoms of decompression sickness.[30] It is unknown whether astronauts need to undergo closure.
Open surgery is used if the PFO is discovered during open heart surgery for another indication such as bypass or valvular surgery.
A permanently deployed double-umbrella device occluding the PFO is deployed through venous access across the interatrial septum. One of the device limbs is deployed in the left atrium with the other in the right atrium. Currently available devices include the Amplatzer (AGA) PFO occluder, the Starflex (NMT Medical) device, Premere (St. Jude), PFO STAR (Cardia), and Helex (Gore).
These devices are introduced through a vein, typically a femoral vein. The device is then advanced in a collapsed state through a sheath placed across the interatrial septum. The sheath is gradually withdrawn and the left atrial side of the device self-expands. The whole apparatus is pulled back until the left atrial side of the device pulls against the septum. The sheath is then further pulled back to expose the right atrial disk, which also self-expands. Once proper positioning is confirmed by x-ray and ultrasound, the device catheter shaft is detached or unscrewed from the device and withdrawn from the body, leaving the device behind. The Food and Drug Administration (FDA) approved the Amplatzer PFO Occluder in 2016 and the Gore Cardioform Septal Occluder in 2018 for PFO closure in the US 'to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke.'
Calls for randomized trial data comparing medical treatment versus device treatment had met with poor enrollment responses.[31] One review of observational studies has suggested benefits of device closure, but the results of the randomized CLOSURE 1 study of >900 patients failed to show a difference in end points between best medical therapy and device closure.[32][33] However, device safety was demonstrated. One randomized controlled trial (RCT) showed no difference in medical therapy versus closure with an Amplatzer device.[34] Both the CLOSURE 1 study and the RCT trial did not achieve the prespecified clinical end point for efficacy and showed nonstatistically significant trends toward benefit with a closure device group for secondary stroke prevention compared with antiplatelet or anticoagulant therapy. Observational studies suggest that anticoagulant therapy may be better than antiplatelet therapy in medically treated patients.[33] Subsequent trials CLOSE and REDUCE compared the efficacy of a closure device to antiplatelet therapy alone and showed significant benefit with closure device use. The DEFENSE PRO trial evaluated the benefit of a closure device in patients with PFO with high-risk features (e.g., large shunt size and atrial septal aneurysm) and did not restrict medical therapy to antiplatelet therapy alone. The results were overwhelmingly positive, favoring the closure device arm. One subsequent meta-analysis of all the RCTs by the American Association of Neurology showed that in patients younger than 60 years with cryptogenic stroke, the PFO procedure is associated with a benefit of an absolute recurrent stroke risk reduction of 3.4% at 5 years, with a periprocedural complication risk of 3.9% and increased absolute rate of nonperiprocedural atrial fibrillation of 0.33% per year.[28] When compared to a similar strategy with anticoagulation therapy, there was no difference in the reduction of ischemic events but there was an associated decrease in bleeding events with the device closure plan. When full anticoagulation and antiplatelet therapies were compared, without a closure device, there was a decrease in ischemic events with full anticoagulation but with an associated increase in major bleeding events.[25]
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